Mutation update for the SATB2 gene

Abstract

SATB2‐associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype‐phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Speech, language, and feeding phenotypes of SATB2‐associated syndrome

“…Except for a single individual (SATB2‐85), remaining participants were included in previous publications detailing their clinical and genetic investigations . Individual SATB2‐85 underwent molecular cytogenetic studies with an array‐based comparative genomic hybridization (CGH) + SNP (4x180, Agilent Technologies, Santa Clara, California).…”

“…SATB2 ‐associated syndrome (SAS) is a multisystem disorder caused by alterations of the SATB2 gene manifesting as craniofacial anomalies and neurodevelopmental problems warranting multidisciplinary assessment and management . The reported craniofacial phenotype in SAS includes facial dysmorphic features, palatal abnormalities (cleft palate, high‐arched palate, submucous cleft palate, bifid uvula), micrognathia, and several dental anomalies .…”

“…Verbal communication is the area of development most severely impacted in SAS . Previous reports indicate that affected individuals often demonstrate significant impairment of verbal communication abilities, receptive and language deficits, reliance on augmentative and alternative communication (AAC) modalities, features potentially consistent with apraxia of speech, and hallmarks of an autism spectrum disorder …”

“…While the development of receptive language abilities beyond those of expressive language have been reported in several individuals, the degree of verbal impairment is reported to be variable, ranging from absent or near absent to more developed, yet still substantially delayed . Furthermore, other comorbid palatal anomalies and feeding difficulties that can have an impact of speech production, have been reported to commonly occur in SAS …”

“…While the development of receptive language abilities beyond those of expressive language have been reported in several individuals, the degree of verbal impairment is reported to be variable, ranging from absent or near absent to more developed, yet still substantially delayed. 3,4 Furthermore, other comorbid palatal anomalies and feeding difficulties that can have an impact of speech production, have been reported to commonly occur in SAS. 1,2,[4][5][6][7][8][9][10][11][12][13][14][15] We here present the first report of speech, language, and feeding difficulties conducted using direct assessments and screening procedures in a large cohort of individuals with SAS from different demographic and genetic backgrounds.…”